INTRODUCTION

At the turn of the twentieth century, granulomatous angiitis of the brain was the prototypical form of a vasculitis restricted to the central nervous system (CNS). The disorder is recognized for its distinctive clinical and laboratory presentation, association with a diverse comorbid illnesses, and the predilection for cerebral vessels of varying caliber, from small meningeal to named cerebral and spinal vessels. A striking and often defining feature of the disorder was progressive headache. The past two decades have witnessed extraordinary progress in understanding of adult and pediatric primary CNS angiitis respectively abbreviated PACNS, cPACNS) in large retrospective, observational cohorts, and patient registries, stratifying cases based upon clinical, neuroradiologic, and histopathological features, leading to insights in management aimed at averting inevitable morbidity and mortality resulting from brain infarction. Part 1 chapter of Headache and the Vasculitides dealt with systemic vasculitides; Part 2 focuses on 10 themes relating primary CNS vasculitis to headache. There is a recent review of adult and pediatric systemic and CNS vasculitides [1]. 

Box 1:

no caption available

THEME 1: THE CLASSIFICATION AND NOSOLOGY OF PRIMARY CNS VASCULITIDES LIKE ITS SYSTEMIC COUNTERPARTS, RESTS UPON THE CALIBER OF VESSELS INVOLVED AND THE UNDERLYING HISTOPATHOLOGY

The 2012 Revised International Chapel Hill Consensus Conference (CHCC) Nomenclature of Vasculitides [2▪▪] has been the most widely used classification for adult vasculitides. It categorizes the clinicopathologic entities based on the involved vessels and updated the nosology of the vasculitic syndromes, using specific descriptive terminology that conveyed pathophysiologic specificity. The Pediatric Rheumatology European Society (PRES) and the European League against Rheumatism (EULAR) in collaboration with the Pediatric Rheumatology International Trials Organization (PRINTO) reported methodology and overall clinical, laboratory and radiographic characteristics for several childhood systemic vasculitides followed by a final validated classification also based upon vessel size, with high sensitivity and specificity [3,4▪▪]. In keeping with this nosology, primary CNS vasculitides may be classified as a single organ vasculitis (SOV) along with vasculitides restricted to the peripheral nervous system (PNS), and aorta (IgG4-aortitis) and related diseases.

Adult [5▪▪] and childhood isolated CNS angiitis (IACNS) [6], PACNS [7▪▪], granulomatous angiitis of the brain (GAB) [8] and GANS; adult [9] and cPACNS [10] are all equivalent terms for prototypical primary vasculitic disorders restricted to the CNS.

PedVas, the Pediatric Vasculitis Initiative (ClinicalTrials.gov Identifier: NCT02006134) and ARCHiVe Investigators collaborating on the multicenter international pilot Registry for Childhood Vasculitis: e-entry [11]; in association with members of the Childhood Arthritis and Rheumatology Research Alliance (CARRA); the web-based network, BrainWorks: The International Childhood CNS Vasculitis Outcome Study (http://www.sickkids.ca/Research/Brainworks/the-brainworks-study/index.html), have been collecting clinical and biobank data of registered cPACNS, systemic and unclassified vasculitis cases for over a decade. The subtypes of cPACNS [12▪▪] are distinguished by vessel size, angiographic and pathologic findings, and the presence or absence of long-term progression. The predilection for the caliber of involved vessels may be predicted by neuroimaging employing magnetic resonance angiography (MRA), computed tomography angiography (CTA) and conventional catheter angiography (CA), and subcategorized into angiography-positive nonprogressive (APNP) and progressive (APP)-cPACNS [13] affecting medium and large vessels, and angiography-negative (AN) small-vessel cPACNS (SVcPACNS) due to affliction of small vessels [14].

THEME 2: PRIMARY CNS VASCULITIDES ARE SUCH EXCEPTIONALLY RARE DISORDERS THAT GLOBAL COOPERATION IS NECESSARY TO ASSEMBLE SUFFICIENT COHORTS TO DERIVE ITS ASSOCIATED EPIDEMIOLOGY

Collaborative, evidence-based, randomized clinical trials (RCTs) and observational cohorts have been undertaken by the French Vasculitis Study Group (FVSG), French NeuroVascular Society (SFNV), and National Society of Internal Medicine (SNFMI databases, United States-Canadian Vasculitis Clinical Research Consortium (VCRC), European Vasculitis Study Society (EUVAS), EULAR, The French Vasculitis Cohort of Patients with Primary Vasculitis of the Central Nervous System (COVAC), and the Diagnostic and Classification Criteria in Vasculitis Study (DCVAS) have all contributed to the epidemiology primary CNS and systemic vasculitides. Attesting to the rarity of PCNSV, DCVAS identified 42 (0.6%) cases of PCNSV among registrant pool of 6991 subjects with diverse forms of systemic and single organ vasculitis among 136 sites from 2011 to 2017 based on standard criteria endorsed by American College of Rheumatology (ACR) and EULAR [15]. There are no reliable incidence or prevalence data [12▪▪], which is problematic for identifying clinical subtypes [16▪▪]. Recent international surveys collecting information on medium and large cPACNS [17] and SV-cPACNS [18] have been shared with international clinician networks, including the German Society for Paediatric Rheumatology, the Paediatric Rheumatology European Society, the “Network Paediatric Stroke,” and members of the ACR/CARRA Registry of Paediatric Rheumatology list servers. This project has shown consensus in numerous diagnostic and therapeutic treatment approaches highlighting key areas to be utilized in the epidemiology, and development of expert standardization of diagnostic and therapeutic approaches in this rare inflammatory brain disease.

THEME 3: FOR ALMOST A CENTURY, CASES OF PRIMARY CENTRAL NERVOUS SYSTEM VASCULITIS WERE DEFINED AT POSTMORTEM EXAMINATION AS GRANULOMATOUS ANGIITIS

In 1922, Harbitz [19] described two patients with a previously unrecognized cerebral vasculitis. At age 26, a woman noted worsening headaches, mental change, and ataxia, culminating two years later in stupor, spastic paraparesis, coma, and death. The other patient, a 46-year-old man, developed hallucinations and confusion progressing to gait difficulty, stupor, coma, and death in 9 months. At postmortem examination, both had granulomatous angiitis of the leptomeninges, composed of lymphocytes, multinucleate giant cells, and epithelioid cells, with vessel necrosis and extension into the brain along involved veins and arteries of varying caliber. In 1959, Cravioto and Fegin [20] delineated the clinicopathologic syndrome of granulomatous angiitis, naming it instead for the distinctive CNS granulomatous vasculitis pathology that included multinucleated giant cells and epithelioid cells. For two more decades, rare affected patients were identified in life presenting with widely divergent systemic and neurological disorders including Hodgkin lymphoma [21], cerebral aneurysm [22], polymyalgia rheumatica [23], shingles [24], and brain tumor [25] but there was no effective treatment.

THEME 4: THE ADVENT OF DIAGNOSTIC ANGIOGRAPHY AND IMMUNOSUPPRESSIVE THERAPY LED INVESTIGATORS TO IDENTIFY AND TREAT LIVING CASES

In 1981, following advances in the classification, laboratory diagnosis, and treatment of systemic vasculitides with induction of remission therapy with cyclophosphamide (CYC) and alternate-day prednisone in pathologically-proven cases of polyarteritis nodosa (PAN) and granulomatous polyangiitis (GPA) [26], Cupps and Fauci [27] articulated the problem of diagnosing living cases of IACNS, suggesting that no single sign, symptom, or laboratory test apart from a diagnostic brain biopsy could confidently establish or rule out the diagnosis. The diagnosis of IACNS was one of exclusion in that similar clinical and angiographic appearances could theoretically be produced by a wide variety of systemic and CNS mimics. Findings in cerebrospinal fluid (CSF) might be compatible with the diagnosis but not themselves diagnostic. The pattern of “beading” or aneurysms in a cerebral angiogram suggested the diagnosis, however causes other than CNS vasculitis might produce a similar radiographic appearance. As a negative angiogram would not exclude the diagnosis when small vessels alone were involved, the authors suggested that any patient presenting with severe headache and impaired mental function and progression to multifocal neurologic deficits without an established diagnosis should be aggressively evaluated by brain biopsy. In 1983, Cupps and coworkers [5▪▪] illustrated the findings of IACNS among four living patients including three defined by angiographic beading (two patients) or “sausage” appearance (one patient), and in another with prototypical granulomatous angiitis (Case 4) of small vessels of the filum terminale in a leptomeningeal biopsy.

By 1987, Calabrese and Mallek [7▪▪] added 8 new cases of so called PACNS to the 40 literature cases emphasizing that suspicion for the diagnosis should be heightened when multifocal symptoms and signs developed in a stepwise progression typically preceded by headache or mental status changes, particularly dementia, so noted respectively in 58% and 63%, and 30% and 13% of the literature and their own cases. The restricted nature of the cerebral vascular changes as defined by classical angiographic (in five cases) and diagnostic neuropathological features in biopsy (in two cases) or postmortem brain tissues (in one case) combined with the success of high-dose immunosuppressive therapy to achieve remission (in seven cases) contrasted with their own Patient 5. A 74-year-old man with mental change, transient hemiparesis and aphasia (although without a stated headache) had a CSF protein of 169 mg/dl with 38 white blood cells (WBCs) and cerebral angiography that showed tortuosity and some irregularity of the lumen of intracranial vessels without segmental or alternating stenosis and ectasia. Yet leptomeningeal and brain biopsy showed GAB affecting small meningeal veins with proliferation of epithelioid cells along vascular walls sparing the cortex. That case exemplified the problem of equating cases of medium- and large-vessel vasculitis ascertained by cerebral angiography with others diagnosed by brain biopsy that continues to impact the validity of PACNS and its clinicopathological subtypes.

THEME 5: BY THE TURN OF THE TWENTIETH CENTURY, GRANULOMATOUS ANGIITIS WAS THE PROTOTYPICAL PRIMARY CENTRAL NERVOUS SYSTEM ANGIITIS

Over the next decade, Younger et al.[8] focused on prototypical GAB and spinal cord in 78 pathologically verified literature cases including 4 patients of their own, all defined by the presence of granulomatous giant cell and epithelioid cell infiltration in the walls of arteries of various caliber, ranging from named cerebral vessels to small arteries and veins at postmortem examination (Fig. 1). One each occurred in association with Hodgkin lymphoma (HL), varicella zoster virus (VZV), neurosarcoidosis, and no associated disorder. Headache was noted at onset in all 4 patients, as well as in 57% of patients with GANS; and during the course of the disease in 78%. Moreover, the combination of headache, encephalopathy or other mental changes, increased CSF protein content with or without pleocytosis followed by hemiparesis, quadriparesis, progressing to lethargy and stupor were predictive of a poor prognosis and mandated the need for combined meningeal and brain biopsy to establish the diagnosis with certainty.

FIGURE 1:

Central nervous system vasculitis. The media and adventitia of a small leptomeningeal artery is almost completely replaced by multinucleated giant cells (arrowheads). There is intimal proliferation with obliteration of the vascular lumen and a dense perivascular mononuclear inflammatory infiltrate (hematoxylin and eosin; original magnification, ×250).

The same authors [28] substituted GANS for GAB to encompass spinal cord cases, and added 12 unreported during the period of 1922 to 1988, including 45 cases published between 1988 and 1997, and one new case for a total of 136 pathologically verified cases diagnosed by brain and meningeal biopsy (in 36 cases) or at postmortem examination (in 100 cases). Headache (in 100%) and mental change (in 78%) typically evolved over weeks to months followed by seizures (in 50%), hemiparesis or tetraparesis (in 36%), with CSF manifesting pleocytosis (in 69%), protein elevation (>100 mg/dl) (in 45%) and normal glucose levels (in 77%). The pathologic heterogeneity of GANS was exemplified by the predilection of lesions for vessels of variable caliber, regardless of the presenting clinical syndrome or associated disorder. Among postmortem studied cases, 12% had predominant involvement of small vessels alone, 78% involved small, medium, and large vessels together, and 10% involved large cerebral vessels alone. Isolated microscopic foci of vascular inflammation noted in heart, lungs, and kidney specimens at general autopsy in 19 cases, was considered insufficient evidence for systemic vasculitis.

There were 51 cases of GANS (37.5%) in association with other conditions, including temporal or generalized giant cell arteritis (TA/GCA) (in 11 cases); VZV (in 12 cases), Hodgkin and non-HL (in 9 cases; 7 alone, and 2 with VZV); sarcoidosis (in 6 cases); amyloid angiopathy (in 10 cases); systemic lupus erythematosus and VZV (in 1 case); and human immunodeficiency virus (HIV) without acquired immune deficiency syndrome (AIDS) (in 2 cases). The neurologic disorder associated with temporal or GCA differed in the predilection for large intracranial vessels, and the relentless progression despite corticosteroids. The neurologic presentation of contralateral hemiparesis associated with VZV typically followed appearance of an ophthalmicus (V1) rash by 2–3 weeks with skin lesions and vasculitic involvement of the ipsilateral carotid, middle or anterior cerebral artery in nine cases. Affected patients with lymphoma had a subacute or chronic neurologic illness often with contemporaneous headaches, with four cases manifesting preceding lymphoma for up to 3 years, and three with occult lymphoma detected only after diagnosis of granulomatous angiitis. The neurologic disease in the six patients with sarcoidosis was essentially similar to other cases of GANS, in that two patients with known systemic disease were being treated with corticosteroids (CS) when neurologic symptoms emerged.

THEME 6: RETROSPECTIVE AND PROSPECTIVE OBSERVATIONAL COHORTS STRATIFIED BY CLINICAL, NEURORADIOGRAPHIC, AND HISTOPATHOLOGICAL FEATURES FACILITATED CLINICOPATHOLOGIC SUBTYPES FOR INSIGHTS INTO TREATMENT AND MANAGEMENT

Between 1983 and 2011, Salvarani et al.[9,29▪] enrolled 163 patients of whom 97 (59.5%) presented with progressive headache and 88 (54%) with cognitive dysfunction. Overall, two-thirds (64%) met inclusion criteria for probable CNS vasculitis based upon cerebral angiography manifesting areas of smooth-wall segmental narrowing or dilatation, and occlusions affecting multiple cerebral arteries without proximal vessel changes of atherosclerosis or other causes. The remaining one-third (36%) met the definite diagnosis based on a CNS tissue biopsy showing transmural vascular inflammation involving leptomeningeal or parenchymal vessels. The latter histopathology was granulomatous in 60%, lymphocytic in 22%, and necrotizing alone in 17%, and were consistent with subsets of the disease rather than different stages of the same process. Overall, there was a favorable response with sustained remission in 72%, and an overall favorable response to therapy in 85% of cases with parenteral and oral CS alone or in association with CYC or other immunosuppressants [including azathioprine (AZA), mycophenolate mofetil (MMF) or biological therapies employing rituximab (RTX) and etanercept]. Overall mortality was 15% often within the first year, especially in those with severe disease and disability. An overall unfavorable outcome was also noted in those with large named vessel involvement and cerebral infarcts at the time of diagnosis, a poor response to treatment, and more frequent relapses.

In 2010, De Boysso et al.[30▪] on behalf of the FVSG, SFNV, and SNFMI enrolled 52 adults in 2010 with PACNS with disease onset ≤15 years, and added 62 patients [31] to ascertain the outcome of various therapeutic strategies in inducing prolonged remission status at followup 12–198 months later. New onset-headaches were noted in 54% of patients including several with a history of migraines, cluster headaches, and thunderclap type headaches. Mortality was 8% with prolonged remission in 66% employing CS and an immunosuppressant or biological agent (AZA, MTX, MMF, RTX) after induction therapy of CS and CYC. With >80% receiving CS combined with CYC compared to 44% in the Mayo series [9,29▪], and no obvious excess mortality in those treated in the Mayo series with CS alone, one obvious difference in the French series was the majority of patients with lymphocytic versus granulomatous histopathology (78% versus 31%) in spite of comparable percentages of large vessel involvement (76% versus 65%), which may have a better outcome and lower mortality.

THEME 7: IMPORTANT TURNING POINTS IN THE UNDERSTANDING OF PRIMARY ADULT CNS VASCULITIDES COINCIDED WITH STROKE NEUROLOGY

The neuroradiological approach to CNS vasculitis has evolved along with the availability of highly precise methods of brain and cerebral vasculature imaging to heighten understanding of the vascular inflammatory process. The pathophysiology of cerebrovascular injury is similar to other vascular beds wherein mural changes lead to vessel stenosis or occlusion and endothelial inflammation promotes intraluminal coagulation and thrombosis [32]. Perivascular inflammatory changes and edema also contribute to the pathologic picture. Arterial and venous components may be involved separately or together and the dural sinuses may be affected. Persistent neurologic deficits, including stroke and headache, were the commonest initial symptoms affecting 68% of 101 studied subjects with PCNSV [9] as defined by diagnostic criteria of Calabrese and Mallek [7▪▪] and modified by Birnbaum and Hellmann [33]. Infarctions were the commonest type of lesion noted with MRI of the brain, which among 53% of 90 subjects so studied, were multiple in appearances in 85% and bilateral in 83%, with cortical and subcortical involvement in 63% overall, suggesting larger artery, branch-artery, and small-artery distributions. Intracranial hemorrhage was noted in 8% of subjects.

Traditional radiologic methodologies do not adequately recognize the major categories of LVV, MVV and SVV as in the systemic circulation. According to Küker [34], vasculitic involvement of the internal carotid (ICA), M1 and A1 segments of the middle (MCA) and anterior cerebral arteries (ACA), intracranial vertebral and basilar arteries, and P1 segment of the posterior cerebral artery (PCA), easily appreciated by as large vessels on noninvasive imaging employing MRA and CTA (Fig. 2a–e), would be equivalent to medium vessels by 2012 Revised Chapel Hill Consensus Conference (CHCC) Nomenclature of Vasculitides [2▪▪]. By contrast, arterial vessels distal to the MCA bifurcation, as well as the anterior (AComm) and posterior communicating (PComm) arteries, still considered MVV by the same CHCC criteria, would not be well visualized alongside intracranial LVV by MRA or CTA, and require CA to assess luminal irregularities. Finally, the smallest muscular arteries and arterioles within the brain parenchyma as well as the capillaries and proximal venules, all considered small vessels by their lumen size, corresponding to a caliber of 200–500 μm or less [35], are all well beneath the resolution of invasive and noninvasive neuroimaging, and instead require tissue biopsy to diagnose vasculitic involvement.

FIGURE 2:

(a–e) Primary angiitis of the central nervous system. (a) Noncontrast CT (top) demonstrates multifocal regions of low attenuation. Those in the right frontal subcortical white matter and left basal ganglia (black arrows) are sharply defined, without mass effect and likely reflect old infarctions. Both the cortex and underlying white matter of the right occipital lobe are involved as is the right splenium of the corpus callosum (white arrows). In these locations, the margins are more ill-defined and there is subtle mass effect characterized by sulcal and ventricular effacement, suggesting acute ischemia in the right posterior cerebral artery territory. MRI FLAIR imaging (middle) demonstrates central low and peripheral high signal intensity within the frontal and periventricular white matter lesions (black arrows) consistent with chronic encephalomalacia from old infarctions. The FLAIR hyperintense signal within the right occipital lobe is more confluent and extends to the posterior temporal lobe and splenium, involving both cortex and white matter (white arrows) and better delineates the extent of the acute infarct. DWI (bottom) demonstrates restricted diffusion consistent with acute ischemia. (b) T1-weighted imaging pre and postgadolinium demonstrates extensive leptomeningeal enhancement along the cortical surface of the posterior temporal and occipital lobes. (c) CTA demonstrates multifocal vascular narrowing within several branches of the MCA (white arrows) with intervening regions of normal appearing vasculature. At the bottom of the image, vascular narrowing within the posterior cerebral artery (not marked) is present. (d and e) CA reveals completely normal extra-cranial vasculature. The anterior cerebral (black arrowheads), middle cerebral (black arrows) and posterior cerebral artery (black outlined arrows) demonstrate mild to severe short segment stenoses. CA, catheter angiography; CT, computed tomography; CTA, computed tomographic angiography; DWI, diffusion-weighted imaging; FLAIR, fluid attenuation inversion recovery; MCA, middle cerebral artery; MRI, magnetic resonance imaging.

Küker [34] described three steps in the diagnostic evaluation of CNS vasculitis beginning with the demonstration of brain lesions by T2- and diffusion and perfusion-weighted (DWI/PWI) MRI, followed by the delineation of underlying vascular pathology by 1.5 Tesla (T) MRA to study the entire course of the carotid and vertebral arteries, as well as the circle of Willis. Time-of-flight (TOF) MRA sequences improves spatial resolution to detect subtle stenosis and mural thickness in basal brain arteries using MRA source images; however, high resolution (hr)MRI will discern mural enhancement. Conventional CA with digital subtraction (DSA) evaluates both medium- and small brain vessels and the status of cerebral hemodynamics. Gomes [36] divides available neuroimaging studies into three groups including those that investigate brain parenchyma, vessel lumen or the vessel wall. Parenchymal findings, while least specific, are necessary to detect the presence of the disease state and to follow progression and remission status. Vessel lumen abnormalities, while highly suggestive of vasculitis in LVV, are generally considered nonspecific in intracranial MVV, and insensitive in SVV.

THEME 8: FURTHER UNDERSTANDING OF CHILDHOOD PRIMARY CNS VASCULITIDES AND PEDIATRIC ACUTE ISCHEMIC STROKE EVOLVED INDEPENDENTLY MAKING COMPARISONS TO ADULTS PROBLEMATIC

Advances in the understanding of cPACNS have occurred independent of childhood acute ischemic stroke (AIS) [12▪▪] emphasizing differences between PACNS, making comparisons difficult for several reasons [37].

First, contrary to antemortem pediatric cases of cerebral vasculitis that show angiographic evidence of large named vessel involvement, children with SV-cPACNS may only be conclusively diagnosed by CNS biopsy tissues that show transmural inflammation of small meningeal and penetrating cortical vessels. Affected patients with SV-cPACNS may present with focal symptoms suggesting an association with AIS, but are more likely to develop subacute, nonlocalizing, neurologic complaints, such as headache, behavioral changes, seizures, school failure, or cognitive decline. Such features make them more like adult cases of GANS [38▪] than PACNS [7▪▪]. Despite these apparent similarities, neither a recent series based upon brain biopsy in cPACNS [39] or scoping review of the cPACNS literature [16▪▪], included histopathology as a prognostic determinant nor mentioned prototypical granulomatous pathology, suggesting a bias of selection.

Second, childhood AIS associated with CNS vasculitis may be highly variable in character and distribution compared to their adult counterparts with a different spectrum of AIS and hemorrhagic stroke due to etiopathogenic differences and maturational factors in the developing cerebral circulation [37]. One such example is the mild preponderance of transient ischemic attacks (TIAs), AIS, seizures and headaches that occur in some pediatric cases of moyamoya disease (MMD) who as adults later emerge with hemorrhagic events due to more developed spontaneous collaterals that in turn are more highly associated with hemorrhagic stroke [40].

Third, both noninvasive and invasive neuroimaging are far less specific in cPACNS than their adult counterparts. Arterial imaging employing CTA and MRA typically shows normal findings even when parenchymal MRI ranges from normal to diffusely abnormal across a wide array of lesion characteristics. Moreover, CA in AIS that fails to show relevant radiographic changes may lead to the presumption of angiography-negative cPACNS [14] suggesting a corresponding caliber of vessel involvement despite unsubstantiated clinicoradiologic or histopathological findings.

Fourth, it is unclear whether the subcategorization of cPACNS by angiographic criteria, including affected vessel size and presence of progression meaningfully differentiates cPACNS into subtypes of AN-SVcPACNS, APP- and APNP-cPACNS. It is also unknown whether children with APNP-cPACNS who present with the abrupt onset of focal or multifocal neurological deficits leading to AIS progress to APP-cPACNS in the absence of immunosuppressant therapy, or derive significant benefit when treated, compared to control subjects who receive standard therapy for AIS alone. Moreover, there is limited data on the reliability of subtype classification in childhood AIS and cerebral vasculopathy. Nomenclature and definitions that vary between different clinical specializations and similar MRI patterns of cerebral vasculopathy have been labeled differently. The most common intracranial arteriopathy in childhood presents as unilateral, focal stenosis in a focal cerebral arteriopathy (FCA) on cranial MRI [41,42]. Referring to the putative transient nature of the stenosis, this specific monophasic, nonprogressive arteriopathy was labeled transient cerebral arteriopathy (TCA) based on childhood AIS [43,44].

Fifth, awaiting the results of the PedVas Initiative of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV), the approach to cPACNS has generally been to lump them into the broader category of IBrainD/IBD [45], while systematically excluding angiography-positive mimics of cPACNS.

Two well designed studies of pediatric AIS, The Vascular Effects of Infection in Pediatric Stroke (VIPS) and the International Pediatric Stroke Study (IPSS) [46,47] that recognize pediatric arteriopathy as unilateral and FCA, have begun to address clinical, neuroimaging and histopathologic characteristics with implications for cPACNS. The minimum neuroimaging protocol for patient inclusion in VIPS consists of MRI with axial DWI, axial T2-weighted images, axial or coronal FLAIR images, and MRA of the brain. Conventional angiography and CTA were accepted in lieu of MRA. Arteriopathy was defined as the imaging appearance of an in situ arterial abnormality (stenosis, irregularity, occlusion, banding, pseudoaneurysm, dissection flap) not attributable to an exogenous thrombus or cardioembolism, and not considered a normal developmental variant [48]. The increased use of vessel wall imaging [49] may further delineate enhancing arterial segments due to inflammation. The commonest childhood arteriopathies in this cohort of children presenting with AIS were MMD, arterial dissection (intracranial and extracranial), and focal cerebral arteriopathy–inflammatory type (FCA-i) including primary diffuse and multifocal cerebral vasculitis. Attesting to the rarity and difficulty in attributing causation to a neuroimaging, primary and secondary vasculitis respectively were the presumed causes of possible arteriopathy in a subgroup of 18 possible arteriopathy cases, representing only 0.6% and 1.1% of the larger cohort.

The IPSS established in 2003 as a multicenter, multinational prospective clinical research registry (ClinicalTrials.gov Identifier: NCT00084292) has been enrolling neonates or children with AIS or are at high risk of having a stroke into the registry. One important purpose has been to develop a comprehensive consensus-based classification system for childhood AIS, and a consensus-based classification of childhood AIS using the Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE) criteria that shows good interrater reliability also with implications for cPACNS (47). The CASCADE criteria cite the aim of eliminating terms with overlapping and/or nonspecific definitions, such as FCA, cPACNS, TCA and steno-occlusive arteriopathy [50,51]. The primary CASCADE classification contains seven subtypes including (i) small vessel arteriopathy (SVA), (ii) FCA, (iii) bilateral cerebral arteriopathy of childhood, (iv) aortic/arteriopathy, (v) cardioembolism, (vi) other, and (vii) multifactorial. It separates cases of FCA and bilateral cerebral arteriopathy that respectively include likely cases of APP- and APNP-cPACNS, and MMD or fibromuscular dysplasia (FMD), from SVA of childhood based upon the acute neurological deficit, and radiographic image of the parenchymal infarct, and confirmed by detailed review of MRA, CTA or CA. Awaiting more definitive clinical studies and with an ever expanding nomenclature, it is difficult to find equivalences in the VIPS and IPSS to cPACNS with exception of the monophasic, nonprogressive form of APNP-cPACNS, which probably accounts for the majority of patients with TCA.

THEME 9: SMALL-VESSEL PRIMARY CHILDHOOD AND ADULT CNS VASCULITIDES CHALLENGE EXPERTS TO REASSESS GUIDING PRINCIPLES IN REACHING A CONSENSUS IN REGARDS DIAGNOSIS, MANAGEMENT AND ETIOPATHOGENESIS

The original criteria of Calabrese and Mallek [7▪▪] have been adapted for cPACNS [13,52] acknowledging advances in, and the clinical similarity of IBrainDs [45] and other neuroimmune CNS disorders, especially those with neuronal autoantibodies and frequent neuropsychiatric manifestations [53]. However, except for rare cases of Hashimoto encephalopathy [54], there are no documented cases of histologically-proven CNS vasculitis in any adult or childhood autoimmune encephalitis [55].

The precision gained in diagnosing adult PACNS by requiring brain biopsy confirmation for case definition (thereby reclassifying definite cases as probable with only consistent findings on angiography and abnormal findings on MRI) [33], was not incorporated into the largest case series of PACNS [30▪,56], except in selective cohorts when neuroimaging was precluded, as in isolated small-vessel vasculitis [57,58]. A majority of clinicians surveyed from the German Society for Pediatric Rheumatology, the Pediatric Rheumatology European Society, Network Pediatric Stroke, and members of the ACR/CARRA Pediatric Rheumatology list server [18] found that while criteria for the diagnosis of SVcPACNS requires histopathologic confirmation [16▪▪], only 46.09% of respondents indicated that they would perform a brain biopsy.

With its distinctive features of severe headache, cognitive decline, focal seizures and ischemic deficits and less unfavorable outcome with immunosuppressive therapy (targeting transmural lymphocytic cell infiltration of small leptomeningeal and brain parenchymal vessels on biopsy), prototypical cases of SVcPACNS seem more similar to adult cases of PACNS and childhood cases of GANS [28] than APNP- or APP-cPACNS. Hunder et al.[59] questioned the premise of Elbers and colleagues [39] that SVcPACNS was a distinct disease citing referral bias in the selection of cases with singular clinical, angiographic and histopathological features, brain biopsy sampling errors, and the possibility that lymphocytic vasculitis of small vessels might be an earlier stage of a progressive disease process that involves other histopathology or vessels of larger caliber. The authors cite the earlier literature case of Yari and colleagues [60] of a 12-year-old boy with progressive headaches, vomiting, perioral dysesthesia, bilateral papilledema, ataxia, focal weakness and brisk reflexes for several months accompanied by CSF pleocytosis. Brain biopsy showed angiitis of small, medium-sized, and larger vessels, however, larger vessel involvement was not advanced or widespread enough to distort the vessels seen on cerebral angiography that was interpreted as normal.

Two other historical cases, one of a very young child and another of a young adult add granularity to the limits of small-vessel CNS vasculitis [61,62]. Marsden [61] reminded readers that giant cell granulomatous angiitis should be considered in children in his description of a 3-year-old girl with a 2-week history of headache, dizziness, focal weakness and decerebration associated with normal cerebral angiography and CSF pleocytosis. Postmortem examination showed acute arteritis with multinucleated giants cells associated with fragmentation of elastic lamina of the basilar artery. Kolodny et al.[62] highlighted the interface between cPACNS and GANS in Case 3 of a 21-year-old student who presented with leg weakness, sensory loss, and hyperactive reflexes, CSF protein 560 mg/dL, and a semiobstructive lesion on myelography from the T11 to the L1 vertebrae which was found at surgery to contain matted pair of T9 to T12 right sided roots. He progressed over several months with headache, mental change, vision loss, and papilledema that responded favorably to larger doses of dexamethasone. A right common carotid artery angiogram showed stretching of a few small vessels in the area of the angular gyrus that was otherwise normal, as was left carotid angiography. When CS side-effects became intolerable, they were discontinued but he became progressively lethargic and lapsed into coma and died. Postmortem examination showed GANS chiefly affecting small vessels including arterioles, venules and capillary-sized vessels of the spine leptomeninges and parenchyma, subarachnoid nerve roots, central retinal veins and intracranial optic nerves.

THEME 10: A COMPARISON OF SMALL-VESSEL CHILDHOOD AND ADULT PRIMARY CNS VASCULITIS SHOWS DISTINCTIVE DIFFERENCES

It has remained unanswered precisely how cases of SV-cPACNS and PACNS compare. A literature cohort analysis [1] of 14 well defined cases of SVcPACNS drawn from the series of Elbers and colleagues [39] with a postmortem case described by Matsell et al.[63] were compared to 39 adults, comprising 5 patients with small-vessel GANS drawn from Case 3 of the series of Younger and coworkers [8], Cases 1 and 2 of the series of Koo and Massey [64], the single case reports of Kattah et al.[65] and Fukasawa et al.[66], 8 cases from the series of angiography-negative PCNSV by Salvarani et al., and isolated adult small-vessel PACNS cases from the prospective multicenter French cohort study [57], to highlight their salient differences and similarities (Table 1). Cases of SV-cPACNS [39] were distinguished from those with GANS [28], angiography-negative PCNVS [58] and PACNS with isolated SVV [57] by prominent seizures and serum markers of inflammation at presentation, less frequent focal neurological deficits (despite equal proportions of AIS on brain CT) and less prominent CSF protein elevation and pleocytosis. Aside from a higher proportion of probable SV-cPACNS cases (14.2%) than adults (2.6%), lymphocytic predominant SV pathology outnumbered granulomatous cases in cPACNS 13 : 1 in comparison to adults in which granulomatous cases outnumber lymphocytic predominance 1.3 : 1. Mortality was increased anecdotally in the absence of any treatment for those in either group, regardless of the histopathology. The present analysis had several weaknesses. The numbers were small, cases were retrospective unmatched for age, disease activity or other variables, neuropathological criteria for cataloguing histopathology in adults [67] and treatment protocols employing empiric immunosuppression in childhood cases [68] were not identical; nor was follow-up uniform, and summary data from case series varied in detail. Five literature cases were excluded from this analysis including 4 angiography-negative biopsy-proven cases of cPACNS [14] because of histologic involvement of small and medium-sized vessels; and one recent case of biopsy-proven small-vessel cPACNS that did not undergo contemporaneous cerebral vascular imaging [69].

Table 1 - Angiography-negative small-vessel primary CNS vasculitis in children and adults Children Adults Presentation No. (%) No. (%) M : F, age range 4 : 10, 6–17 y 22 : 17, 18–75 y Duration of symptoms 1 d–2 y 17 d–4 y Headache 9 (64.2) 19 (48.7) Mental change 8 (57.1) 25 (64.1) Seizures 10 (71.4) 21 (53.8) Focal neurological deficit 4 (28.5) 24 (61.5) CSF protein elevationa 7 (50) 32 (91.4) CSF pleocytosis 10 (71.4) 30 (85.7) Elevated systemic Inflammatory markers 12 (85.7) 10 (25.6) AIS on neuroimaging 3 (21.4) 1 (20) Angiography negativeb 14 (100) 32 (100) Histopathology  Definite vasculitis 12 (85.7) 38 (97.4)  Probable vasculitis 2 (14.3) 1 (2.6)  Lymphocytic 13 (92.9) 16 (41)  Granulomatous 1 (7.1) 22 (56)  Acute necrotizing 0 1 (3) Outcome  Died 2 (14.3) 4 (10.3)  Unchanged or relapsed 0 13 (33.3)  Improved 12 (85.7) 22 (56.4) Treatment  None 0 1 (2.6)  CS 0 5 (12.8)  CS + IS 14 (100) 31 (79.5)  IS 0 2 (5.1) Reproduced from reference [1].No., number; %, percentage; M, male; F, female, CSF, cerebrospinal fluid; AIS, acute ischemic stroke; CS, corticosteroids; d, days; IS, other immunosuppressant; y, years.

aCSF performed in 14 children and 35 adults.

b7/32 adults had MRA.

Finally, in comparison to adults, it is difficult to reconcile the use of cytotoxic therapy for any subtype of childhood primary CNS vasculitis given the disappointing results of systemic trials for childhood AAVs that found a rate of remission status of only 42% and visceral organ damage in 63% in its study cohort employing CYC for remission induction [70]. Even with modifications in the treatment regimens over the past several years, systemic outcome remains relatively poor with nearly half of patients (45%) experiencing one or more clinical relapses despite significant improvements in rate of remission at the end of the induction period (80.4%), despite substantial chronic kidney disease (54.8% at 1 year) and clinically significant adverse events (in 54%) leading to treatment modifications (typically requiring dose reduction of CYC or switching to RTX). As prospective studies are needed to assess the most appropriate therapeutic modality for individual children with AAV [71], the same can be said for cPACNS and its subtypes.

CONCLUSION

Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Headache may be an important clue to vasculitic involvement of CNS vessels. There is general agreement on several principles in the approach to vasculitis especially primary CNS types. First, it is a potentially serious disorder with a propensity for permanent disability owing to tissue ischemic and infarction. Second, cerebral angiography is a reliable and reproducible method of diagnosis in large vessels but misses small vessel involvement, thus the absence of evidence of suspected findings does not exclude widespread small vessel involvement. Third, confirmation of arteritis should be obtained in suspected children and adults through biopsy of brain and meninges. Fourth, undiagnosed and therefore untreated, CNS vasculitides are often fatal. Fifth, clinicians must therefore choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, cautioned by serious and potentially lethal side effects.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

REFERENCES 1. Younger DS. Adult and childhood vasculitis. Handb Clin Neurol 2023; 195:653–704. 2▪▪. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum 2013; 65:1–11. 3. Ruperto N, Ozen S, Pistorio A, et al. EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part I. Overall methodology and clinical characterisation. Ann Rheum Dis 2010; 69:790–797. 4▪▪. Ozen S, Pistorio A, Iusan SM, et al. Paediatric Rheumatology International Trials Organization (PRINTO). EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II. Final classification criteria. Ann Rheum Dis 2010; 69:798–806. 5▪▪. Cupps TR, Moore PM, Fauci AS. Isolated angiitis of the central nervous system. Prospective diagnostic and therapeutic experience. Am J Med 1983; 74:97–105. 6. Lanthier S, Lortie A, Michaud J, et al. Isolated angiitis of the CNS in children. Neurology 2001; 56:837–842. 7▪▪. Calabrese LH, Mallek JA. Primary angiitis of the central nervous system. Report o